Amyloid β-Peptide Inhibits Neuronal Glucose Uptake by Preventing Exocytosis

Abstract

Amyloid β peptide (Aβ) is suspected as a contributing factor for decreased glucose utilization in the brain of Alzheimer's patients; however, little is known about the regulatory mechanism of neuronal glucose uptake and how Aβ affects such a mechanism. We report that membrane depolarization by 40 mM KCl increases both neuronal glucose uptake and immunolabeling of the exofacial epitope of glucose transporter isoform GLUT3, suggesting that fusion of GLUT3 vesicles with the plasma membrane increases glucose uptake. Aβ25-35 decreased neuronal glucose uptake and this decrease was prevented by exocytosis-enhancing compounds (40 mM KCl, 50 μM ruthenium red). Aβ25-35 also inhibited exocytosis of the fluorescent membrane dye FM1-43 at neuronal cell bodies; however, 40 mM KCl was effective in overcoming this Aβ inhibition. Furthermore, GLUT3 colocalized with SNARE (N-ethylmaleimide-sensitive factor attached protein receptor) complex proteins (SNAP-25 and Syntaxin 1), and cleavage of the v-SNARE, VAMP, reduced glucose uptake. Our findings suggest that neuronal glucose uptake is regulated by SNARE complex-dependent docking and fusion of GLUT3 vesicles with the plasma membrane and that Aβ decreases glucose uptake by inhibiting fusion of these vesicles.